DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The amendment filed 05/07/2026 has been entered. Claims 1, 3, 6-14 and 29 are pending and are under examination. Claims 4-5 and 15-28 have been cancelled. Claim 3 has been amended.
Status of Claims 9 and 10: The footnote of Applicants’ reply on page 5 of 13 of the remarks filed 05/07/2026 states that claims 9 and 10 were not addressed elsewhere in the Office’s arguments, as such Applicant assumes that claims 9 and 10 are deemed allowable once the independent claim 1 is determined to be allowable.
In response, there were no arguments presented by the Office in the Non-Final action mailed 1/8/2026. Only rejections were presented in the Non-Final action mailed 1/8/2026. In the Non-Final Office action at the top of page 6, claim 9 and claim 10 were rejected as follows:
“Claim 9: Frazer et al does not disclose the composition comprises Clostridium novyi.” This meets the limitation of claim 9, wherein the composition does not comprise Clostridium novyi.
“Claim : 1. Frazer et al does not disclose that the attenuated Salmonella comprises a lysis gene or cassette operably linked to an intracellularly induced Salmonella promoter.” This meets the limitation of claim 10, wherein the attenuated Salmonella do not comprise a lysis gene or cassette operably linked to an intracellularly induced Salmonella promoter.
The current status of claims 1, 9 and 10 are rejected.
Claim Rejections Withdrawn
The rejection of claim 4 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn in view of the cancellation of claim 4.
The rejection of claims 3 and 4 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in view of the amendment to claim 3 and the cancellation of claim 4.
The rejection of claim 4 under 35 U.S.C. 102(a)(1) as anticipated by Frazer et al. WO 2006/108241 10/19/2006 as evidenced by Cao et al US 2012/0157401 is withdrawn in view of the cancellation of claim 4.
Claim Rejections - 35 USC § 102 and 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The rejection of claim(s) 1, 3, 6 and 9-10 under 35 U.S.C. 102(a)(1) as anticipated by or, in the Frazer et al. WO 2006/108241 10/19/2006 as evidenced by Cao et al US 2012/0157401 is maintained.
Claim 1. Frazer et al disclose a method of a treating a subject having or at risk of having a benign nervous system tumor, the method comprising administering to the subject a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria (paragraph 110),
Thus, Frazer et al disclose treatment of neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), schwannomatosis or any combination thereof.
Claim 3: Frazer et al disclose the subject has N1, NF2, schwannomatosis or any combination thereof which are not a malignant solid tumor, thus the subject also does not have a malignant solid tumor.
Claim 6: Frazer et al disclose the attenuated Salmonella is administered intravenously.
Claim 9: Frazer et al does not disclose the composition comprises Clostridium novyi.
Claim : 10. Frazer et al does not disclose that the attenuated Salmonella comprises a lysis gene or cassette operably linked to an intracellularly induced Salmonella promoter.
Applicant’s Argument
Applicant respectfully submits that Frazer does not provide an enabling disclosure.
First, Frazer is generally toward methods that "comprise administering to the subject an effective amount of an immune stimulator and an inhibitor of IL-10 function...." Frazer, [0012] (emphasis added). To achieve these methods, Frazer "contemplates the use in the compositions of the invention of any antigen that corresponds to at least a portion of a target antigen of interest for stimulating an immune response to the target antigen." Frazer, [0069]. In some embodiments, that includes "use of antigen-presenting cells, which present an antigen corresponding to at least a portion of the target antigen...." Frazer, [0104]. Frazer proceeds to disclose methods of making an antigen-presenting cells (see Frazer, [0107]-[0112]) and suggests that "an antigen may be linked to, or otherwise associated with, a cytolysin to enhance the transfer of the antigen into the cytosol of an antigen-presenting cell...." Frazer, [0109]. Frazer then states that "the cytolysin and antigen are provided in the form of a delivery vehicle such as, but not limited to, a liposome or a microbial delivery vehicle selected from virus, bacterium, or yeast." Frazer, [0110]. Frazer then provides a list of suitable bacteria for providing the cytolysin and antigen, stating:
A wide variety of nonvirulent, non-pathogenic bacteria may be used; preferred microbes are relatively well characterized strains, particularly laboratory strains of E. coli, such as MC4100, MC1061, DH5a, etc. Other bacteria that can be engineered for the invention include well-characterized, nonvirulent, nonpathogenic strains of Listeria monocytogenes, Shigella flexneri, mycobacterium, Salmonella, Bacillus subtilis, etc.
Frazer, [0110]. This is the only disclosure of Salmonella in a composition for use in the methods disclosed in Frazer. Here, Salmonella is provided by Frazer as one of eight "bacteria" that can be used as a for providing a cytolysin and an antigen in a method of making an antigen-presenting cell which, once made, the antigen-presenting cell is used in combination with an IL-10 inhibitor to treat "a range of conditions including pathogenic infections and cancers." Frazer, abstract. A person of skill in the art ("POSA") would not conclude from Frazer - who discloses Salmonella once in the entire disclosure as one of eight bacteria a POSA could choose from for use in making one element of a combination composition - that administering Salmonella alone would treat any disease, much less the particular claimed disease.
Second, Frazer provides "a method for treatment and/or prophylaxis of a disease or condition, comprising administering to a patient in need of such treatment an effective amount of an inhibitor of IL-10 function, together with an effective amount of an immune stimulator" (Frazer, [0143]) and then proceeds to recite a laundry list of examples of "cancers" in paragraph [0143]. All told, over 150 examples of different cancers are listed in this paragraph by Frazer. Of those cancers, "neurofibromatosis" is recited once throughout the entirety of the Frazer reference. Merely because one particular disease (e.g., neurofibromatosis) is mentioned in a laundry list of diseases, a person skilled in the art would not conclude that the disclosed methods in Frazer can be used for treating the particular claimed disease. Further, as conceded by the Office, of the more than 150 types of cancers disclosed, Frazer fails to recite neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), or schwannomatosis - the specific benign nervous system tumors that the claimed methods treat.
Response to Applicants’ Argument
Applicants’ argument has been carefully considered but is not found persuasive.
A prior art reference provides an enabling disclosure and thus anticipates a claimed invention if the reference describes the claimed invention in sufficient detail to enable a person of ordinary skill in the art to carry out the claimed invention; "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006) (citing Rasmusson v. SmithKline Beecham Corp., 413 F.3d 1318, 1326, 75 USPQ2d 1297, 1302 (Fed. Cir. 2005)).
The claims are drawn to a method of a treating a subject having or at risk of having a benign nervous system tumor, the method comprising administering to the subject a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria, wherein the benign nervous system tumor is neurofibromatosis 1 (NF 1); neurofibromatosis 2 (NF2); schwannomatosis; or any combination thereof.
Frazer et al disclose a method steps of the instant claims by the disclosure of treating a subject having or at risk of having a benign nervous system tumor, the method comprising administering to the subject a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria (paragraph 110),by Cao et al the types of neurofibromatosis are neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) and schwannomatosis.
The disclosure of Frazer provides sufficient guidance to direct one of ordinary skill in the art as of the effective filing date of the instant invention to administer a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria to subject having or at risk of having neurofibromatosis which as evidenced by Cao et al neurofibromatosis encompasses neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) and schwannomatosis.
Frazer gives instructions on how to administer e.g. intravenously a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria to subject having or at risk of having neurofibromatosis and thus Frazer is an enabling disclosure for administering a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria to subject having or at risk of having neurofibromatosis which as evidenced by Cao et al neurofibromatosis encompasses neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) and schwannomatosis.
In addition, "proof of efficacy is not required for a prior art reference to be enabling for purposes of anticipation." Impax Labs. Inc. v. Aventis Pharm. Inc., 468 F.3d 1366, 1383, 81 USPQ2d 1001, 1013 (Fed. Cir. 2006). See MPEP 2121.
Applicants argument that Salmonella and neurofibromatosis is mentioned once in Frazer and Salmonella is provided by Frazer as one of eight "bacteria" and that over 150 different cancers are mentioned in Frazer and that POSA would be required to first pick from the multiple bacteria listed as mere components for making one half of the disclosed composition of Frazer and pick from over 150 types of cancer listed in Frazer has been carefully considered but is not found persuasive.
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. See MPEP 2123. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See MPEP 2123. A reference that clearly names the claimed species anticipates the claim no matter how many other species are named. See MPEP 2131.02 (II).
Th rejection of claim(s) 1 and 7 under 35 U.S.C. 103 as being unpatentable over Frazer et al. WO 2006/108241 10/19/2006 as evidenced by Cao et al US 2012/0157401 in view of Portnoy et al. US 6004815 12-21-1999 is maintained.
Frazer et al disclose a method of a treating a subject having or at risk of having a benign nervous system tumor, the method comprising administering to the subject a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria (paragraph 110),
Thus, Frazer et al disclose treatment of neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), schwannomatosis or any combination thereof.
Frazer et al does not disclose the Salmonella is Salmonella typhimurium.
Portnoy et al teaches that Salmonella typhimurium can be used as an intracellular delivery vehicle. See whole of Portnoy et al especially table 1.
It would have been prima facie obvious to a person of ordinary skill in the art as of the effective filing date of the instant invention to have modified Frazer et al to use live attenuated Salmonella typhimurium for intracellular delivery in the manner disclosed by Frazer et al for treating neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) and schwannomatosis, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Frazer et al discloses the live attenuated Salmonella for treating neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2) and schwannomatosis and Portnoy et al disclose that Salmonella typhimurium can be used as an intracellular delivery vehicle.
Response to Applicant’s Argument.
Applicant argues:
As discussed above, Frazer describes methods that "comprise administering to the subject an effective amount of an immune stimulator and an inhibitor of IL-10 function " Frazer, [0012] (emphasis added). Thus, a POSA reading Frazer would have therefore understood that the compositions as disclosed are formulated specifically for the two active ingredients disclosed therein. As such, the Office's use of Frazer for allegedly teaching a "method comprising administering to the subject a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria" (Office Action, p. 7), stands in direct opposition to the MPEP, which directs that references used in obviousness combinations must be considered in their entirety. MPEP § 2414.02. Thus, the Office cannot pick and choose select disclosures in Frazer that allegedly establish that only Salmonella bacteria can effectively treat a "cancer" without considering that Frazer, as a whole, only disclosed compositions comprising both an IL-10 inhibitor and an immune stimulator (which, as detailed above, the immune stimulator may be an antigen-presenting cell prepared with a bacteria, for example a Salmonella bacteria, but not necessarily the bacteria itself). There is nothing in Cao and/or Portnoy that would encourage a POSA to modify the combination composition of Frazer to only include a Salmonella bacteria for use according to the claimed methods.
Response:
Applicant argument has been carefully considered but is not found persuasive.
The claims are drawn to a method of a treating a subject having or at risk of having a benign nervous system tumor, the method comprising administering to the subject a therapeutically effective amount of a composition comprising live attenuated Salmonella bacteria, wherein the benign nervous system tumor is neurofibromatosis 1 (NF 1); neurofibromatosis 2 (NF2); schwannomatosis; or any combination thereof.
The claims as written is open-ended and does not exclude additional components in the composition being administered to the subject and does not exclude additional method steps. In addition, the instant claims do not recite that only the live attenuated Salmonella bacteria is administered to treat cancer and nor do the claims specifically recite that the live attenuated Salmonella does not comprise heterologous genes. The salmonella of the combination of Frazer and Portnoy is live attenuated even though it is being used as a delivery vehicle and therefore meets the limitation of “live attenuated Salmonella”.
The open-endedness of the claimed method allows for other components in the composition and thus, the claims as written is not exclusively drawn to only the live attenuated Salmonella bacteria present in the composition treating the benign nervous system tumor.
Applicants argument:
Further, Frazer mentions that administering an effective amount of an immune stimulator and an inhibitor of IL-10 would be applicable to "a range of conditions including pathogenic infections and cancers" (Frazer, abstract) and provides a laundry list of over 150 types of cancers that could be treated by the disclosed methods (Frazer, [0143]) - none of which are the benign nervous system tumors NF1, NF2, and/or schwannomatosis as presently claimed. In regard to the inclusion of "neurofibromatosis" in this list (and the Office's further use of Cao to identify a neurofibromatosis as NF1, NF2, and/or schwannomatosis), Applicant respectfully submits that impermissible hindsight and "picking and choosing" elements from a laundry list of cancers in Frazer was used in an attempt to arrive at the claimed invention, and there would not have been any reasonable expectation of one of skill in the art successfully doing SO. Frazer provides no direction that would lead a skilled artisan to even select "neurofibromatosis" from the extensive list of cancers, much less specifically select NF1, NF2, and/or schwannomatosis as presently claimed.
Response to Applicants’ Argument:
Applicant's arguments filed has been fully considered but they are not persuasive.
Applicants argument regarding picking and choosing from a laundry list of over 150 types of cancers and picking and choosing Salmonella from a list of 8 bacteria that can be used as delivery vehicles in Frazer has been addressed above.
In response to applicant's argument that the inclusion of "neurofibromatosis" in this list (and the Office's further use of Cao to identify a neurofibromatosis as NF1, NF2, and/or schwannomatosis) and that impermissible hindsight and "picking and choosing" elements from a laundry list of cancers in Frazer was used in an attempt to arrive at the claimed invention is not found persuasive.
Arguments regarding Frazer and impermissible hindsight is not found persuasive because Frazer anticipates claim 1 and impermissible hindsight is relevant to obviousness not anticipation as Frazier anticipates the method of claim 1.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Applicants argument:
Portnoy does not describe bacteria as the active agent for use in a composition, but instead the bacteria is disclosed as a means to deliver an active agent. As shown in Table 1 of Portnoy, Salmonella typhimurium is one of eight examples of microbial delivery systems used for delivering active agents. Although Portnoy may suggest that the microbial delivery systems can be used to deliver "anti-cancer agents (e.g. cyclin dependent kinase (CDK) inhibitors such as P16, P21 or P27)" (Portnoy, 3:63-65), Portnoy fails to teach or suggest that Salmonella typhimurium alone treat any cancer, much less a benign nervous system tumor such as NF1, NF2, and/or schwannomatosis as claimed. Thus, there is nothing in Portnoy that would motivate one of skill in the art to modify the methods of Frazer to use only Salmonella typhimurium as an active agent for treating the benign nervous system tumors as claimed, nor would a POSA have any reasonable expectation of success at doing so based on these two references for at least the reasons described above.
Response:
Applicants argument has been carefully considered but is not found persuasive. Applicants argument that Portnoy fails to teach or suggest that Salmonella typhimurium alone treat any cancer, much less a benign nervous system tumor such as NF1, NF2, and/or schwannomatosis as claimed is not found persuasive. As stated above, claim 1 as written is open-ended and does not exclude other components in the administered composition and thus claim 1 and dependent claims are not limited to using live attenuate Salmonella alone to treat a benign nervous system tumor such as NF1, NF2, and/or schwannomatosis.
The rejection of claim(s) 1, 7, 8, 11-14 and 29 under 35 U.S.C. 103 as being unpatentable over Frazer et al. WO 2006/108241 10/19/2006 as evidenced by Cao et al US 2012/0157401 in view of Thanos et al. US 2019/0017050 1/17/19 cited in IDS is maintained.
Frazer et al as evidenced by Cao et al is set forth above but does not disclose the use of a live attenuated Salmonella typhimurium strain VNP20009 which has a modified lipid A (msbB-) and purine autotrophic mutation (purI) as disclosed by the instant specification. Frazer et al as evidenced by Cao et al does not disclose further administering the live attenuated bacteria in combination with an immune checkpoint inhibitor and/or an angiogenesis inhibitor.
Thanos et al disclose the use of live attenuated Salmonella typhimurium VNP20009 in treating cancer/tumors (see abstract, paragraph 9, 17, 20, 71 and 414-415).
Thanos et al disclose the live attenuated Salmonella typhimurium is administered with checkpoint inhibitor is an antibody that binds PD-L1 or CTLA-4. See paragraph 71.
Thanos et al discloses live attenuated Salmonella typhimurium is administered with Bevacizumab an anti-VEGF antibody. See paragraph 414-415.
It would have been prima facie obvious to a person of ordinary skill in the art to have modified the method of Frazer et al by administering live attenuated Salmonella typhimurium such as strain VNP20009 and further administering an immune checkpoint inhibitor and/or an angiogenesis inhibitor as taught by Thanos et al, thus resulting in the instant invention with a reasonable expectation of success. The motivation to do so is that Thanos et al disclose that live attenuated Salmonella typhimurium such as VNP20009 can be used in treating cancer/tumors and as a combination therapy an immune checkpoint inhibitor and/or an angiogenesis inhibitor is administered.
Response to Applicants Argument:
Applicant argues:
Like Frazer, Thanos mentions that immunostimulatory bacteria would be applicable to "treating all types of tumors, including cancers" and provides a laundry list of over 100 types of tumors that could be treated by the disclosed methods. Thanos, paragraphs [0485-0488]. Despite these extensive lists including examples of "tumors of the central nervous system" (see paragraph [0488]), it is not explicitly clear that these include benign tumors. Notably, the only disclosure of benign tumors provided by Thanos are "leiomyomas (benign tumors of smooth muscle)" and "rhabdomyomas (benign tumors of skeletal muscle)." Thanos, paragraph [0487].
Response:
Applicants argument has been carefully considered but is not found persuasive.
This is because Thanos et al disclose that the Salmonella is immunostimulatory for anti-cancer therapy. Thanos et al disclose VNP20009 is immunostimulatory (paragraph 61) and when administered with checkpoint inhibitor e.g. antibody that binds PD-L1 or CTLA-4 (see paragraph 71) or administered with Bevacizumab an anti-VEGF antibody (se paragraph 414-415) can be used to treat cancers and malignancies.
Thus, one of ordinary skill in the art as of the effective filing date of the instant invention would have a reasonable expectation of success of using VNP20009 in combination with a checkpoint inhibitor or with Bevacizumab an anti-VEGF antibody to treat the cancer disclosed by Frazer et al.
Status of Claims
Claims 1, 3, 6-14 and 29 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/OLUWATOSIN A OGUNBIYI/Primary Examiner, Art Unit 1645
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